Eosinophilic oesophagitis (EoE) is a chronic progressive inflammatory condition of the
oesophagus first described in 1978 but not recognised as distinct diagnosis until 1993,
affecting both children and adults. It is characterised by eosinophilic infiltration of
the oesophageal epithelium and can lead to difficulty swallowing, oesophageal strictures,
food bolus obstruction, and symptoms mimicking gastro-oesophageal reflux disease (GORD).
23% adults with dysphagia and 50% with food bolus obstruction are diagnosed with EoE,
meaning it is a common condition encountered by Gastroenterologists. Recent systematic
reviews have estimated that EoE has a pooled prevalence of 28-34 per 100,000 population,
but the incidence has risen remarkably over the past four decades.
EoE can occur at any age, with a rising incidence in children and adults aged 30-50 years
and studies have shown that it can significantly impact on health related quality of life
by impairing social and psychological functioning. It is more common in males and in
those with allergic conditions such as asthma, eczema and rhinitis, suggesting a food or
aeroallergen trigger. Diagnosis is obtained by gastroscopy with a minimum of six
oesophageal biopsies recommended by international guidelines, due to its potentially
patchy distribution. Hallmark endoscopic appearances of the oesophagus have been
described and include oesophageal rings, longitudinal furrows, oedema, exudate, and
narrowing. Oesophageal biopsies must show > 15 eosinophils (eos) per high powered field
(HPF) infiltrating the oesophageal mucosa, as to not be mistaken with other conditions
such as GORD which may also exhibit eosinophilic infiltration but at lower numbers. Other
histological features include eosinophil micro-abscesses, basal zone hyperplasia, dilated
intercellular spaces, eosinophil surface layering, papillary elongation and lamina
propria fibrosis.
Once a diagnosis has been made, treatment of EoE is with food elimination diets, proton
pump inhibitors (PPI), or topical glucocorticoids, such as budesonide orodispersible
tablet (BOT). In a small subgroup of patients, immunomodulatory drugs such as
azathioprine or 6-mercaptopurine might be required, and research is ongoing into
monoclonal antibody therapy. The aim of treatment, as described in recent European and
American Gastroenterological Association (AGA) and Joint Task Force on Allergy Immunology
Practice Parameters (JTF) guidelines, is to alleviate symptoms, prevent stricture
formation and achieve histological remission with < 15 eos/HPF infiltration.
Previous studies have shown that PPI may induce remission in 42% patients. Budesonide
orodispersible table (BOT) may induce remission in 85% patients, but can be associated
with the side effect of candidiasis in up to 10% patients. An empiric 6-food (dairy,
wheat, soy, eggs, nuts, and seafood/shellfish) elimination diet induces histological
remission in around 75% of patients, whereas a 4-food elimination diet (dairy, wheat,
soy, and egg) induced histological remission in around 50% patients, and a 2-food
elimination diet (dairy and wheat) may be effective for 40% patients. Elemental diet
(amino acids) induces histological remission in 90% of patients but is impractical and
only recommended for consideration after failure of medical therapy or elimination diets.
Prolonged avoidance of dietary triggers may lead to drug-free sustained clinical and
histological remission. Once a stricture has developed then endoscopic balloon dilatation
may be required and can improve dysphagia in up to 75% of adults with oesophageal
strictures, and is relatively safe with a perforation rate of only 1%, but has no effect
on the underlying inflammatory process.
Systematic review with meta-analysis found no statistical difference between PPI and BOT,
however there are few head to head studies comparing the treatments and long term
evidence for BOT is still lacking; indicating the need for further prospective studies.
European guidelines therefore currently do not favour one treatment over another and
state that the choice of therapy should be individually discussed with the patient and
may be interchangeable over time. Treatment effectiveness should be assessed with repeat
gastroscopy with oesophageal biopsies after 6-12 weeks.
Gastroscopy involves placing a thin flexible camera into a patient's mouth and advancing
it to the oesophagus, stomach and duodenum. The procedure takes approximately 5 minutes,
during which biopsy forceps are placed through a 2.8mm channel on the standard
gastroscope to obtain oesophageal mucosal biopsies for histological analysis. Although
topical anaesthetic may be applied to the back of the throat and intravenous sedation
given, for many patients, gastroscopy remains an unpleasant and daunting experience.
Transnasal endoscopy (TNE) has more recently been developed and potentially offers
patients a more comfortable procedure due to the reduced diameter of the gastroscope, but
due to the need for lifelong surveillance, there has been a move for even less invasive
and less costly methods.
The GI string test (EnteroTestTM) was first developed in 1970 for sampling microorganisms
from the small intestine. The original test involved swallowing a small, weighted gelatin
capsule to which a string was attached and the other end taped to the patients cheek. The
capsule reaches the duodenum where it detaches and is excreted naturally and the string
left in situ overnight. The string is then pulled out via the mouth and can be analysed.
Over the years it has been used to analyse biliary composition, culture intestinal
tuberculosis, and profile the distinct microbiome in the oesophagus using 16S rRNA gene
sequencing, as accurately as with mucosal biopsy.
The potential for oesophageal string testing (EST) to monitor EoE activity has been
suggested by a previous study using an overnight swallowed string test in 41 children
correlated with EoE activity on biopsy, which could distinguish between active EoE,
treated EoE, GORD and normal oesophagus, using measured ESGP (eosinophil secondary
granule proteins)
- - including major basic protein 1 (MBP1), esosinophil peroxidase (EPX),
eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP).
Also measured
was the Chacot-Leyden crystal protein/galectin-10 (CLC/Gal-10), which is a primary
cytosolic protein but is also present in the eosinophil's primary (coreless) granule.
Each granule-associated protein carries different biochemical and functional properties
relevant to proposed pathogenic mechanisms for oesophageal dysfunction and remodelling in
EoE. These biomarkers were found to be elevated uniquely in active EoE, compared to
treated EoE, GORD and normal controls.
Another previous study performed a one hour string test on 134 people with EoE or healthy
control, comparing levels of eosinophil associated protein (EAP) including eotaxin-2
(Eot2), eotaxin-3 (Eot3), and MBP on EST to mucosal biopsy. Ackerman showed that these
EST-captured eosinophil-associated biomarkers were proportionate on EST and mucosal
biopsy levels, and also correlated with EoE activity as defined by mucosal eosinophil
counts. These proteins on EST therefore had excellent sensitivity and specificity for
identifying active EoE. They also surveyed patients, and 92% adults preferred the EST
over gastroscopy to monitor their EoE.
Whilst these studies have shown the potential of intraluminal oesophageal biomarkers to
reflect EoE activity, additional research is required to further characterise their
relation to disease activity, correlation with symptoms and response to different
treatments, which has not yet been described in the literature. This knowledge may
improve our understanding of the pathogenesis of EoE and lead to new therapeutic targets
in future, as well as reduce the need for surveillance endoscopy in EoE, which would be
safer and more convenient for patients, and offer cost savings for healthcare resources.
The role of the microbiome is increasingly been appreciated in the development of immune
mediated disease such as EoE, yet to date there are only a handful of studies on the
oesophageal microbiome, finding distinct changes in EoE compared to GORD, adenocarcinoma
and healthy patients. Further research in this area would be interesting to establish if
the microbiome is different in active EoE vs.#46;remission, and how this may affect disease
severity and symptoms, which again may lead to new therapeutic targets in future.
In addition, it is not known whether people with EoE have altered sensitivity in their
oesophagus as part of the remodelling from the chronic inflammatory process. If sensation
is increased this could lead to increased symptoms and if it is reduced then this coud
lead to undiagnosed conditions including strictures and GORD. The calcitonin gene related
peptide has recently been shown to be a marker of oesophageal sensory nerves, and has
been shown to be closer to the oesophageal lumen in oesophageal hypersensitivity, however
its relation to EoE has not yet been examined.
In this study the investigators will sample oesophageal biomarkers and the microbiome
from adults with EoE, using a 30 minute string test, which will be performed on the same
day as their routine gastroscopy an addition to validated symptom questionnaires. The
investigators will repeat the string test after treatment courses with PPI, budesonide or
dietary elimination, alongside their routine gastroscopy. During their gastroscopy the
investigators will also take biopsies to check for the density and positioning of CGRP,
to see if this is different in active and inactive EoE. The aim is to correlate
biomarkers, CGRP and microbiome with endoscopic EoE activity and symptoms, to assess for
changes in response to different treatments. and again may provide further insight into
disease pathogenesis and lead to new therapeutic targets in future.
